Publications by authors named "Mariangela Pucci"

36 Publications

Polyphenols and Cannabidiol Modulate Transcriptional Regulation of Th1/Th2 Inflammatory Genes Related to Canine Atopic Dermatitis.

Front Vet Sci 2021 5;8:606197. Epub 2021 Mar 5.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.

Canine atopic dermatitis (AD) is a multifactorial allergic disease associated with immune and abnormal skin barrier dysfunction and it is one of the primary causes of pruritus. Using a novel model of AD, here we tried to revert the alteration of transcriptional regulation of AD canine key genes testing a nutraceutical mixture containing flavonoids, stilbene, and cannabinoids, which are already well-known for their applications within dermatology diseases. The nutraceutical mixture induced in inflamed cells a significant downregulation ( < 0.05) of the gene expression of , and in keratinocytes and of , and in monocytes. Consistent with the observed alterations of , and messenger RNA (mRNA) levels, a significant increase ( < 0.05) of DNA methylation at specific CpG sites on the gene regulatory regions was found. These results lay the foundation for the use of these natural bioactives in veterinary medicine and provide a model for deeper understanding of their mechanisms of action, with potential translation to human research.
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http://dx.doi.org/10.3389/fvets.2021.606197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982812PMC
March 2021

Epigenetic regulation of DAT gene promoter modulates the risk of externalizing and internalizing behaviors on a normative population: An explorative study.

Behav Brain Res 2021 May 18;406:113246. Epub 2021 Mar 18.

Center for Behavioral Science and Mental Health - Istituto Superiore di Sanità, Rome, Italy; Faculty of Psychology - Uninettuno University, Rome, Italy. Electronic address:

Accumulating research addressed epigenetic modifications and their role on behavioral phenotypes. We recently proposed to study methylation dynamics of two CpG motifs within the 5'-UTR of dopamine transporter (DAT) gene. Starting from a normative population sample of young adults, we selected three sub-groups based on their prevalent symptoms: subjects were assigned to Internalizing, Externalizing and Low-risk sub-groups according to elevated scores in specific phenotypic scales. Using a new approach, we calculated three independent matrixes of cross-correlation between CpG methylation levels, one within each phenotypic sub-group, to determine in which dynamics did the sub-groups differ. We found specific cross-correlation patterns in Externalizing (CpG1, 2 and 3, opposite to the methylation at CpG6) and Internalizing individuals (CpG1 methylation opposite to CpG2, 3 and 6), while Low-risk individuals could follow both trends. The aim of our study was to look for a specific DAT methylation pattern, providing a biomarker that allows early identification of the risk for psycho-pathological deviance.
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http://dx.doi.org/10.1016/j.bbr.2021.113246DOI Listing
May 2021

On the Role of Central Type-1 Cannabinoid Receptor Gene Regulation in Food Intake and Eating Behaviors.

Int J Mol Sci 2021 Jan 1;22(1). Epub 2021 Jan 1.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo TE, Italy.

Different neuromodulatory systems are involved in long-term energy balance and body weight and, among these, evidence shows that the endocannabinoid system, in particular the activation of type-1 cannabinoid receptor, plays a key role. We here review current literature focusing on the role of the gene encoding type-1 cannabinoid receptors in the CNS and on the modulation of its expression by food intake and specific eating behaviors. We point out the importance to further investigate how environmental cues might have a role in the development of obesity as well as eating disorders through the transcriptional regulation of this gene in order to prevent or to treat these pathologies.
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http://dx.doi.org/10.3390/ijms22010398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796374PMC
January 2021

Involvement of DAT1 Gene on Internet Addiction: Cross-Correlations of Methylation Levels in 5'-UTR and 3'-UTR Genotypes, Interact with Impulsivity and Attachment-Driven Quality of Relationships.

Int J Environ Res Public Health 2020 10 29;17(21). Epub 2020 Oct 29.

Department of Dynamic and Clinical Psychology, Sapienza University of Rome, I-00186 Rome, Italy.

Internet influences our communication, social and work interactions, entertainment, and many other aspects of life. Even if the original purpose was to simplify our lives, an excessive and/or maladaptive use of it may have negative consequences. The dopamine transporter (DAT1) gene was studied in relation to addictions, including excessive use of the Internet. The crucial role of DAT1 was previously underlined in modulating emotional aspects, such as affiliative behaviors. The present research follows a new approach based on cross-correlation between (de)methylation levels in couples of CpG loci, as previously shown. We investigated the possible relationships between Internet addiction, impulsivity, quality of attachment, DAT1 genotypes (from the 3'-untranslated region (UTR) variable number of tandem repeats (VNTR) poly-morphism), and the dynamics of methylation within the 5'-UTR of the DAT1 gene. From a normative sample of 79 youths, we extrapolated three subgroups a posteriori, i.e., one "vulnerable" with high Internet Addiction Test (IAT) scores (and high Barrat Impulsivity Scale (BIS) scores; = 9) and two "controls'' with low BIS scores and 10/10 vs. 9/x genotype ( = 12 each). Controls also had a "secure" attachment pattern, while genotypes and attachment styles were undistinguished in the vulnerable subgroup (none showed overt Internet addiction). We found a strongly positive correlation in all groups between CpG2 and CpG3. An unsuspected relationship between the 3'-UTR genotype and a 5'-UTR intra-motif link was revealed by CpG5-CpG6 comparison. The negative correlation between the CpG3-CpG5 positions was quite significant in the control groups (both with genotype 10/10 and with genotype 9/x), whereas a tendency toward positive correlation emerged within the high IAT group. In conclusion, future attention shall be focused on the intra- and inter-motif interactions of methylation on the CpG island at the 5'-UTR of DAT1.
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http://dx.doi.org/10.3390/ijerph17217956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663088PMC
October 2020

Cross-correlations between motifs in the 5'-UTR of DAT1 gene: Findings from Parkinson's disease.

Adv Biol Regul 2020 12 11;78:100753. Epub 2020 Sep 11.

Faculty of Psychology - UTIU Università Telematica Internazionale "Uninettuno", Rome, Italy; Reference Center for Behavioral Science and Mental Health - Istituto Superiore di Sanità, Rome, Italy. Electronic address:

Parkinson's disease (PD) is a neuro-degenerative disorder affecting the striatal motor system, caused by the loss of neuronal cells in the mid-brain, where reduced amounts of dopamine do cause involuntary movements and others symptoms. Alterations of methylome have been reported in PD epigenomic studies, and also human dopamine transporter gene (DAT1, SLC6A3) is considered as a candidate risk factor for PD. Since the DNA methylation on DAT promoter may well have a role in the development of this disease, we aimed to further assess the epigenetic control, by focusing on specific CpG sites located in the 5'-untranslated region (5'-UTR) of the DAT1 gene. Significant changes in DAT 5'-UTR methylation were already found in peripheral blood mononuclear cells (PBMCs) of PD subjects (Rubino et al., 2020). Of note, methylation values at the CpG 5 were increased. We run on same data a novel statistical approach: cross-correlation between pairs of loci. CpG 5 was the only always-differing variable but, alternatively, CpGs 2 and 6 or CpGs 1 and 3 were also significantly correlated with CpG 5. Interestingly, this picture emerged for those patients whose M2xM6 index was above-median; loci were rather independent for below-median patients. Present data may shed light into dynamics occurring at 5'-UTR of DAT1, a gene involved in PD but also in many psycho-physiological pathologies.
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http://dx.doi.org/10.1016/j.jbior.2020.100753DOI Listing
December 2020

Search for an epigenetic biomarker in ADHD diagnosis, based on the DAT1 gene 5'-UTR methylation: a new possible approach.

Psychiatry Res 2020 09 30;291:113154. Epub 2020 May 30.

Faculty of Psychology - Università Telematica Internazionale "Uninettuno", Rome, Italy; Center for Behavioral Science and Mental Health - Istituto Superiore di Sanità, Rome, Italy. Electronic address:

Attention Deficit/Hyperactivity Disorder (ADHD) is the most common neuro-developmental alteration in childhood. To date, its diagnosis is exclusively clinical, however recent studies focused on searching for objective biomarkers. We recently reported a selective alteration of DNA methylation in the 5'-UTR of dopamine transporter (DAT1) gene, in a CGGCGGCGG and a CGCG motif, for ADHD patients (compared to controls). Presently, we looked for DNA methylation of the corresponding CpG sites but complementary on the opposite strand ("COS"). Exploiting a novel cross-correlation approach, we found a core M5 - M5 COS and M2 - M2 COS relationship with relatively free M1 and M6 COS extremes. Our data might be relevant, to find a new biomarker to diagnose ADHD in affected subjects.
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http://dx.doi.org/10.1016/j.psychres.2020.113154DOI Listing
September 2020

Selective alterations in endogenous opioid system genes expression in rats selected for high ethanol intake during adolescence.

Drug Alcohol Depend 2020 07 28;212:108025. Epub 2020 Apr 28.

Università degli Studi di Teramo, Teramo, Italy; Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden. Electronic address:

Historically, the roots of alcoholism have been linked to either environment or heredity. However, the interaction between these factors is still largely unexplored. The evidence supports a link between alcohol consumption and the endogenous opioid system. We here studied the opioid genes expression in male and female Wistar rats derived from a short-term breeding program which selected -- at adolescence -- for high (ADHI line) or low (ADLO line) ethanol drinking. Specifically, in this work we analyzed central opioid gene expression in the rats of the second filial generation (S-ADLO and S-ADHI). Selective downregulation of pronociceptin (Pnoc) and its receptor (Oprl1) mRNA levels were observed in the prefrontal cortex of male S-ADHI rats when compared to S-ADLO, and for Oprl1 also in the nucleus accumbens. An increase in gene expression was instead observed for pro-opiomelanocortin (Pomc) in the nucleus accumbens of S-ADHI males when compared to S-ADLO, as well as for mu opioid receptor (Oprm1) but in females. The differences in mRNA levels may be due to the different alcohol consumption between the two groups of rats or may represent pre-existing differences between them. Moreover, we show a sex-specific modulation of the expression of these genes, thus pointing out the importance of sex on ethanol responses. The results might lead to more specific and effective pharmacological treatments for alcoholism.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108025DOI Listing
July 2020

Epigenetic regulation of the cannabinoid receptor CB1 in an activity-based rat model of anorexia nervosa.

Int J Eat Disord 2020 05 10;53(5):432-446. Epub 2020 Apr 10.

Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.

Objective: Both environmental and genetic factors are known to contribute to the development of anorexia nervosa (AN), but the exact etiology remains poorly understood. Herein, we studied the transcriptional regulation of the endocannabinoid system, an interesting target for body weight maintenance and the control of food intake and energy balance.

Method: We used two well-characterized animal models of AN: (a) the activity-based anorexia (ABA) model in which rats, housed with running wheels and subjected to daily food restriction, show reductions in body weight and increase in physical activity; (b) the genetic anx/anx mouse displaying the core features of AN: low food intake and emaciation.

Results: Among the evaluated endocannabinoid system components, we observed a selective and significant down-regulation of the gene encoding for the type 1 cannabinoid receptor (Cnr1) in ABA rats' hypothalamus and nucleus accumbens and, in the latter area, a consistent, significant and correlated increase in DNA methylation at the gene promoter. No changes were evident in the anx/anx mice except for a down-regulation of Cnr1, in the prefrontal cortex.

Discussion: Our findings support a possible role for Cnr1 in the ABA animal model of AN. In particular, its regulation in the nucleus accumbens appears to be triggered by environmental cues due to the consistent epigenetic modulation of the promoter. These data warrant further studies on Cnr1 regulation as a possible target for treatment of AN.
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http://dx.doi.org/10.1002/eat.23271DOI Listing
May 2020

Methylation of Brain Derived Neurotrophic Factor (BDNF) Val66Met CpG site is associated with early onset bipolar disorder.

J Affect Disord 2020 04 3;267:96-102. Epub 2020 Feb 3.

Karolinska Institute, Clinical Neuroscience, Solna, Sweden. Electronic address:

Background: The brain-derived neurotrophic factor (BDNF) rs6265 (Val66Met) Met allele is associated with early onset (≤ 19 years old) bipolar disorder (BD). Val66Met (G196A) creates a CpG site when the Val/G allele is present. We sought to study the methylation of the BDNF promoter and its interaction with Val66Met genotype in BD.

Methods: Sex/age-matched previously genotyped DNA samples from BD-Type 1 cases [N = 166: early onset (≤ 19 years old) n = 79, late onset (> 20 years old) n = 87] and controls (N = 162) were studied. Pyrosequencing of four CpGs in Promoter-I, four CpGs in promoter-IV, and two CpGs in Promoter-IX (CpG2 includes G= Val allele) was performed. Logistic regression adjusting for batch effect was used to compare cases vs. controls. Analyses also included stratification by disease onset and adjustment for Val66Met genotype. Secondary exploratory analyses for the association of life stressors, comorbid substance abuse, and psychotropic use with methylation patterns were performed.

Results: Comparing all BD cases vs. controls and adjusting for Val66Met genotype, BD cases had significantly higher methylation in promoter -IX/CPG-2 (p = 0.0074). This was driven by early onset cases vs. controls (p = 0.00039) and not late onset cases vs. controls (p = 0.2).

Limitation: Relatively small sample size.

Conclusion: Early onset BD is associated with increased methylation of CpG site created by Val=G allele of the Val66Met variance. Further studies could include larger sample size and postmortem brain samples in an attempt to replicate these findings.
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http://dx.doi.org/10.1016/j.jad.2020.02.002DOI Listing
April 2020

Preclinical and Clinical Evidence for a Distinct Regulation of Mu Opioid and Type 1 Cannabinoid Receptor Genes Expression in Obesity.

Front Genet 2019 14;10:523. Epub 2019 Jun 14.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.

Among endogenous signaling networks involved in both rewarding and homeostatic mechanisms of obesity, a relevant role is played by the endocannabinoid (ECS) and the opioid (EOS) systems. We here studied the transcriptional regulation of ECS and EOS genes in the hypothalamus of Diet-induced obesity rats, a preclinical model of obesity, as well as in humans with obesity and healthy controls. A significant and selective increase in type 1 cannabinoid receptor gene () expression was observed at the beginning of obesity development (5 weeks on high fat diet) as well as after 21 weeks of high diet exposure. After 5 weeks on high fat diet, selective up-regulation of mu opioid receptor gene () expression was also observed. Consistently, epigenetic studies showed a selective and significant decrease in DNA methylation at specific CpG sites at both gene promoters in overweight rats, but only after 5 weeks on high fat diet. Moreover, significantly lower levels of DNA methylation were observed at selected CpG sites of both receptor gene promoters, analyzed in peripheral blood mononuclear cells from younger (<30 years old) humans with obesity, as well as in those with shorter time length from disease onset. Taken together, we here provide evidence of selective, synergistic and time-dependent transcriptional regulation of and genes in overweight rats, as well as in human subjects. These alterations in genes regulation could contribute to the development of the obese phenotype, and we thus suggest and epigenetic modulation as possible biomarkers of obesity development. Due to the reversible nature of the epigenetic hallmark, our data might also open new avenue to early environmental strategies of intervention.
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http://dx.doi.org/10.3389/fgene.2019.00523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588048PMC
June 2019

Regulation of adenosine A receptor gene expression in a model of binge eating in the amygdaloid complex of female rats.

J Psychopharmacol 2019 12 4;33(12):1550-1561. Epub 2019 Jun 4.

School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.

Background: Pharmacological treatment approaches for eating disorders, such as binge eating disorder and bulimia nervosa, are currently limited.

Methods And Aims: Using a well-characterized animal model of binge eating, we investigated the epigenetic regulation of the A Adenosine Receptor (AAR) and dopaminergic D2 receptor (D2R) genes.

Results: Gene expression analysis revealed a selective increase of both receptor mRNAs in the amygdaloid complex of stressed and restricted rats, which exhibited binge-like eating, when compared to non-stressed and non-restricted rats. Consistently, pyrosequencing analysis revealed a significant reduction of the percentage of DNA methylation but only at the AAR promoter region in rats showing binge-like behaviour compared to the control animals. Focusing thus on AAR agonist (VT 7) administration (which inhibited the episode of binge systemically at 0.1 mg/kg or intra-central amygdala (CeA) injection at 900 ng/side) induced a significant increase of AAR mRNA levels in restricted and stressed rats when compared to the control group. In addition, we observed a significant decrease in AAR mRNA levels in rats treated with the AAR antagonist (ANR 94) at 1 mg/kg. Consistent changes in the DNA methylation status of the AAR promoter were found in restricted and stressed rats after administration of VT 7 or ANR 94.

Conclusion: We confirm the role of AAR in binge eating behaviours, and we underline the importance of epigenetic regulation of the AAR gene, possibly due to a compensatory mechanism to counteract the effect of binge eating. We suggest that AAR activation, inducing receptor gene up-regulation, could be relevant to reduction of food consumption.
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http://dx.doi.org/10.1177/0269881119845798DOI Listing
December 2019

Exploring the role of BDNF DNA methylation and hydroxymethylation in patients with obsessive compulsive disorder.

J Psychiatr Res 2019 07 6;114:17-23. Epub 2019 Apr 6.

University of Milan, Department of Biomedical and Clinical Sciences Luigi Sacco, Milano, Italy; CRC "Aldo Ravelli", University of Milan, Milano, Italy; Department of Psychiatry and Behavioral Sciences, Stanford University, CA, USA. Electronic address:

Obsessive-compulsive disorder (OCD) is a clinically heterogeneous neuropsychiatric condition associated with profound disability, whose susceptibility, stemming from genetic and environmental factors that intersect with each other, is still under investigation. In this perspective, we sought to explore the transcriptional regulation of Brain Derived Neurotrophic Factor (BDNF), a promising candidate biomarker in both development and etiology of different neuropsychiatric conditions, in peripheral blood mononuclear cells from OCD patients and healthy controls. In particular, we focused on BDNF gene expression and interrogated in depth DNA methylation and hydroxymethylation at gene promoters (exons I, IV and IX) in a sample of OCD patients attending a tertiary OCD Clinic to receive guidelines-recommended treatment, and matched controls. Our preliminary data showed a significant increase in BDNF gene expression and a significant correlation with changes in the two epigenetic modifications selectively at promoter exon I, with no changes in the other promoters under study. We can conclude that transcriptional regulation of BDNF in OCD engages epigenetic mechanisms, and can suggest that this is likely evoked by the long-term pharmacotherapy. It is important to underline that many different factors need to be taken into account (i.e. age, sex, duration of illness, treatment), and thus further studies are mandatory to investigate their role in the epigenetic regulation of BDNF gene. Of note, we provide unprecedented evidence for the importance of analyzing 5-hydroxymethylcytosine levels to correctly evaluate 5-methylcytosine changes.
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http://dx.doi.org/10.1016/j.jpsychires.2019.04.006DOI Listing
July 2019

Transcriptional regulation of the endocannabinoid system in a rat model of binge-eating behavior reveals a selective modulation of the hypothalamic fatty acid amide hydrolase gene.

Int J Eat Disord 2019 01 22;52(1):51-60. Epub 2018 Dec 22.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.

Objective: Binge-eating episodes are recurrent and are defining features of several eating disorders. Thus binge-eating episodes might influence eating disorder development of which exact underlying mechanisms are still largely unknown.

Methods: Here we focused on the transcriptional regulation of the endocannabinoid system, a potent regulator of feeding behavior, in relevant rat brain regions, using a rat model in which a history of intermittent food restriction and a frustration stress induce binge-like palatable food consumption.

Results: We observed a selective down-regulation of fatty acid amide hydrolase (faah) gene expression in the hypothalamus of rats showing the binge-eating behavior with a consistent reduction in histone 3 acetylation at lysine 4 of the gene promoter. No relevant changes were detected for any other endocannabinoid system components in any brain regions under study, as well as for the other epigenetic mechanisms investigated (DNA methylation and histone 3 lysine 27 methylation) at the faah gene promoter.

Discussion: Our findings suggest that faah transcriptional regulation is a potential biomarker of binge-eating episodes, with a relevant role in the homeostatic regulation of food intake.
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http://dx.doi.org/10.1002/eat.22989DOI Listing
January 2019

Gene expression profiling in adipose tissue of Sprague Dawley rats identifies olfactory receptor 984 as a potential obesity treatment target.

Biochem Biophys Res Commun 2018 11 5;505(3):801-806. Epub 2018 Oct 5.

Department of Medicine, University of Leipzig, 04103, Leipzig, Germany; Leipzig University Medical Center, IFB AdiposityDiseases, University of Leipzig, 04103, Leipzig, Germany. Electronic address:

The aim of the study was to identify and functionally characterize novel candidate gene/s involved in the development of resistance to diet-induced obesity in rats. In a high-fat-diet (HFD) study of rats, we found subgroups which either developed resistance to HFD-induced obesity (DR) or showed an obesity-prone phenotype (DIO). Gene expression analysis in 10 samples (5 DIO vs 5 DR) was performed. The most promising gene, OR6C3 (orthologous with rat Olr984 and mouse Olfr788) was measured by qRT-PCR in paired samples of human visceral (Vis) and subcutaneous (SC) adipose tissue (AT) (n = 225) and in sub-fractions of adipocytes and cells of stromal vascular fraction. Gene expression analyses showed Olr984 with significantly reduced mRNA expression in DR rats. In the Vis AT of human samples we found an up-regulation of OR6C3 compared to SC AT, independent of gender, glucose tolerance or type 2 diabetes. We observed significantly lower levels of SC AT OR6C3 mRNA in subjects with obesity compared to those with normal-weight or overweight. OR6C3 is more expressed in SVF than in adipocytes. Olr984 could be a novel candidate gene related to diet-induced obesity in rats. Variation in human AT mRNA expression is related to obesity parameters and glucose homeostasis and linked to the regulatory role of insulin on the Olr984.
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http://dx.doi.org/10.1016/j.bbrc.2018.09.137DOI Listing
November 2018

Environmental stressors and alcoholism development: Focus on molecular targets and their epigenetic regulation.

Neurosci Biobehav Rev 2019 11 11;106:165-181. Epub 2018 Jul 11.

Faculty of Bioscience, University of Teramo, Teramo, Italy; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Alcohol exposure and stressful events in life can induce long-lasting changes in physiology, behavior and gene expression patterns, eventually facilitating the development of psychiatric diseases like alcohol use disorders (AUD). Epigenetic mechanisms have been recently proposed to play a role in the cellular actions of alcohol via chromatin remodeling. Here we discuss interactions between stress and the pharmacological effects of alcohol, including the possibility that early exposure to, or withdrawal of, alcohol might induce stressful effects of their own. A specific aim is to describe novel molecular mechanisms by which stress, alcohol or their combined presentation impact on the epigenome. A key question is why only a fraction of the population progresses from regular, non-problematic, alcohol use to AUD, despite suffering from similar alcohol exposure. It is important to analyze how environmental factors, most notably stress, interact with the epigenetic machinery to increase vulnerability for AUD. The knowledge derived from this endeavor will be critical for the development of preventive strategies and new, drug- or gene-based, therapies.
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http://dx.doi.org/10.1016/j.neubiorev.2018.07.004DOI Listing
November 2019

Prenatal ethanol induces an anxiety phenotype and alters expression of dynorphin & nociceptin/orphanin FQ genes.

Prog Neuropsychopharmacol Biol Psychiatry 2018 07 18;85:77-88. Epub 2018 Apr 18.

Instituto de Investigación Médica M. y M. Ferreyra (INIMEC-CONICET-Universidad Nacional de Córdoba), Córdoba C.P. 5000, Argentina; Facultad de Psicología, Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address:

Animal models have suggested that prenatal ethanol exposure (PEE) alters the κ opioid receptor system. The present study investigated the brain expression of dynorphin and nociceptin/orphanin FQ related genes and assessed anxiety-like behavior in the light-dark box (LDB), shelter-seeking and risk-taking behaviors in the concentric square field (CSF) test, and ethanol-induced locomotion in the open field (OF), in infant or adolescent Wistar rats that were exposed to PEE (0.0 or 2.0 g/kg, intragastrically, gestational days 17-20). We measured brain mRNA levels of prodynorphin (PDYN), κ opioid receptors (KOR), the nociceptin/orphanin FQ opioid peptide precursor prepronociceptin (ppN/OFQ) and nociceptine/orphanin FQ receptors (NOR). Prenatal ethanol exposure upregulated PDYN and KOR mRNA levels in the ventral tegmental area (VTA) in infant and adolescent rats and KOR mRNA levels in the prefrontal cortex in infant rats. The changes in gene expression in the VTA were accompanied by a reduction of DNA methylation at the PDYN gene promoter, and by a reduction of DNA methylation at the KOR gene promoter. The PEE-induced upregulation of PDYN/KOR in the VTA was accompanied by lower NOR gene expression in the VTA, and lower PDYN gene expression in the nucleus accumbens. PEE rats exhibited hypolocomotion in the OF, greater avoidance of the white and brightly lit areas in the LDB and CSF, and greater preference for the sheltered area in the CSF test. These results suggest that PEE upregulates the dynorphin system, resulting in an anxiety-prone phenotype and triggering compensatory responses in the nociceptin/orphanin FQ system. These findings may help elucidate the mechanisms that underlie the effects of PEE and suggest that the dynorphin and nociceptin/orphanin FQ systems may be possible targets for the prevention and treatment of PEE-induced alterations.
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http://dx.doi.org/10.1016/j.pnpbp.2018.04.005DOI Listing
July 2018

Regulation of gene transcription in bipolar disorders: Role of DNA methylation in the relationship between prodynorphin and brain derived neurotrophic factor.

Prog Neuropsychopharmacol Biol Psychiatry 2018 03 19;82:314-321. Epub 2017 Aug 19.

Department of Psychiatry, Università degli Studi di Milano, Fondazione IRRCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy; Department of Psychiatry and Behavioral Sciences, Bipolar Disorders Clinic, Stanford University, CA, USA. Electronic address:

Bipolar Disorder (BD) is a prevalent and disabling condition, determined by gene-environment interactions, possibly mediated by epigenetic mechanisms. The present study aimed at investigating the transcriptional regulation of BD selected target genes by DNA methylation in peripheral blood mononuclear cells of patients with a DSM-5 diagnosis of type I (BD-I) and type II (BD-II) Bipolar Disorders (n=99), as well as of healthy controls (CT, n=42). The analysis of gene expression revealed prodynorphin (PDYN) mRNA levels significantly reduced in subjects with BD-II but not in those with BD-I, when compared to CT. Other target genes (i.e. catechol-O-methyltransferase (COMT), glutamate decarboxylase (GAD67), serotonin transporter (SERT) mRNA levels remained unaltered. Consistently, an increase in DNA methylation at PDYN gene promoter was observed in BD-II patients vs CT. After stratifying data on the basis of pharmacotherapy, patients on mood-stabilizers (i.e., lithium and anticonvulsants) were found to have lower DNA methylation at PDYN gene promoter. A significantly positive correlation in promoter DNA methylation was observed in all subjects between PDYN and brain derived neurotrophic factor (BDNF), whose methylation status had been previously found altered in BD. Moreover, among key genes relevant for DNA methylation establishment here analysed, an up-regulation of DNA Methyl Transferases 3b (DNMT3b) and of the methyl binding protein MeCP2 (methyl CpG binding protein 2) mRNA levels was also observed again just in BD-II subjects. A clear selective role of DNA methylation involvement in BD-II is shown here, further supporting a role for BDNF and its possible interaction with PDYN. These data might be relevant in the pathophysiology of BD, both in relation to BDNF and for the improvement of available treatments and development of novel ones that modulate epigenetic signatures.
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http://dx.doi.org/10.1016/j.pnpbp.2017.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859566PMC
March 2018

Potential for diagnosis versus therapy monitoring of attention deficit hyperactivity disorder: a new epigenetic biomarker interacting with both genotype and auto-immunity.

Eur Child Adolesc Psychiatry 2018 Feb 18;27(2):241-252. Epub 2017 Aug 18.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.

In view of the need for easily accessible biomarkers, we evaluated in ADHD children the epigenetic status of the 5'-untranslated region (UTR) in the SLC6A3 gene, coding for human dopamine transporter (DAT). We analysed buccal swabs and sera from 30 children who met DSM-IV-TR criteria for ADHD, assigned to treatment according to severity. Methylation levels at six-selected CpG sites (among which, a CGGCGGCGG and a CGCG motif), alone or in combination with serum titers in auto-antibodies against dopamine transporter (DAT aAbs), were analysed for correlation with CGAS scores (by clinicians) and Conners' scales (by parents), collected at recruitment and after 6 weeks. In addition, we characterized the DAT genotype, i.e., the variable number tandem repeat (VNTR) polymorphisms at the 3'-UTR of the gene. DAT methylation levels were greatly reduced in ADHD patients compared to control, healthy children. Within patients carrying at least one DAT 9 allele (DAT 9/x), methylation at positions CpG2 and/or CpG6 correlated with recovery, as evident from delta-CGAS scores as well as delta Conners' scales ('inattentive' and 'hyperactive' subscales). Moreover, hypermethylation at CpG1 position denoted severity, specifically for those patients carrying a DAT 10/10 genotype. Intriguingly, high serum DAT-aAbs titers appeared to corroborate indications from high CpG1 versus high CpG2/CpG6 levels, likewise denoting severity versus recovery in DAT 10/10 versus 9/x patients, respectively. These profiles suggest that DAT 5'UTR epigenetics plus serum aAbs can serve as suitable biomarkers, to confirm ADHD diagnosis and/or to predict the efficacy of treatment.
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http://dx.doi.org/10.1007/s00787-017-1040-9DOI Listing
February 2018

Genetic variation and epigenetic modification of the prodynorphin gene in peripheral blood cells in alcoholism.

Prog Neuropsychopharmacol Biol Psychiatry 2017 06 21;76:195-203. Epub 2017 Mar 21.

Karolinska Institutet, Department of Clinical Neuroscience, Center for Molecular Medicine, Stockholm, Sweden.

Dynorphins are critically involved in the development, maintenance and relapse of alcoholism. Alcohol-induced changes in the prodynorphin gene expression may be influenced by both gene polymorphisms and epigenetic modifications. The present study of human alcoholics aims to evaluate DNA methylation patterns in the prodynorphin gene (PDYN) promoter and to identify single nucleotide polymorphisms (SNPs) associated with alcohol dependence and with altered DNA methylation. Genomic DNA was isolated from peripheral blood cells of alcoholics and healthy controls, and DNA methylation was studied in the PDYN promoter by bisulfite pyrosequencing. In alcoholics, DNA methylation increased in three of the seven CpG sites investigated, as well as in the average of the seven CpG sites. Data stratification showed lower increase in DNA methylation levels in individuals reporting craving and with higher levels of alcohol consumption. Association with alcoholism was observed for rs2235751 and the presence of the minor allele G was associated with reduced DNA methylation at PDYN promoter in females and younger subjects. Genetic and epigenetic factors within PDYN are related to risk for alcoholism, providing further evidence of its involvement on ethanol effects. These results might be of relevance for developing new biomarkers to predict disease trajectories and therapeutic outcome.
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http://dx.doi.org/10.1016/j.pnpbp.2017.03.012DOI Listing
June 2017

Estrogenic suppression of binge-like eating elicited by cyclic food restriction and frustrative-nonreward stress in female rats.

Int J Eat Disord 2017 06 23;50(6):624-635. Epub 2017 Feb 23.

School of Pharmacy, Pharmacology Unit, University of Camerino, 62032, Italy.

Because binge eating and emotional eating vary through the menstrual cycle in human females, we investigated cyclic changes in binge-like eating in female rats and their control by estrogens. Binge-like eating was elicited by three cycles of 4 days of food restriction and 4 days of free feeding followed by a single frustrative nonreward-stress episode (15 min visual and olfactory exposure to a familiar palatable food) immediately before presentation of the palatable food. Intact rats showed binge-like eating during the diestrous and proestrous phases of the ovarian cycle, but not during the estrous (periovulatory) phase. Ovariectomized (OVX) rats not treated with estradiol (E2) displayed binge-like eating, whereas E2-treated OVX rats did not. The procedure did not increase signs of anxiety in an open-field test. OVX rats not treated with E2 that were subjected to food restriction and sacrificed immediately after frustrative nonreward had increased numbers of cells expressing phosphorylated extracellular signal-regulated kinases (ERK) in the central nucleus of the amygdala (CeA), paraventricular nucleus of hypothalamus (PVN), and dorsal and ventral bed nuclei of the stria terminalis (BNST) compared with nonrestricted or E2-treated rats. These data suggest that this female rat model is appropriate for mechanistic studies of some aspects of menstrual-cycle effects on emotional and binge eating in human females, that anxiety is not a sufficient cause of binge-like eating, and that the PVN, CeA, and BNST may contribute to information processing underlying binge-like eating.
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http://dx.doi.org/10.1002/eat.22687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500915PMC
June 2017

A preliminary study of endocannabinoid system regulation in psychosis: Distinct alterations of CNR1 promoter DNA methylation in patients with schizophrenia.

Schizophr Res 2017 10 17;188:132-140. Epub 2017 Jan 17.

Department of Neuroscience, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Psychiatry and Behavioral Sciences, Bipolar Disorders Clinic, Stanford University, CA, USA. Electronic address:

Compelling evidence supports the involvement of the endocannabinoid system (ECS) in psychosis vulnerability. We here evaluated the transcriptional regulation of ECS components in human peripheral blood mononuclear cells (PBMCs) obtained from subjects suffering from bipolar disorder, major depressive disorder and schizophrenia, focusing in particular on the effects of DNA methylation. We observed selective alterations of DNA methylation at the promoter of CNR1, the gene coding for the type-1 cannabinoid receptor, in schizophrenic patients (N=25) with no changes in any other disorder. We confirmed the regulation of CNR1 in a well-validated animal model of schizophrenia, induced by prenatal methylazoxymethanol (MAM) acetate exposure (N=7 per group) where we found, in the prefrontal cortex, a significant increase in CNR1 expression and a consistent reduction in DNA methylation at specific CpG sites of gene promoter. Overall, our findings suggest a selective dysregulation of ECS in psychosis, and highlight the evaluation of CNR1 DNA methylation levels in PBMCs as a potential biomarker for schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2017.01.022DOI Listing
October 2017

Down-regulation of serotonin and dopamine transporter genes in individual rats expressing a gambling-prone profile: A possible role for epigenetic mechanisms.

Neuroscience 2017 01 24;340:101-116. Epub 2016 Oct 24.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

Gambling Disorder (GD) is characterized by excessive gambling despite adverse consequences on individual functioning. In spite of some positive findings, it is difficult to draw any conclusion on the genetics of GD. Indeed, beyond DNA sequence variation, other regulatory mechanisms (like those that engage epigenetics) may explain gene alterations in this addictive disease. Wistar male rats underwent an operant task for the evaluation of individual propensity to gamble. Few rats, after having learnt to prefer nose-poking for a large over a small food reward, were sacrificed to obtain a baseline profile of gene expression at both central and peripheral levels. In the remaining rats, probability of occurrence of large-reward delivery decreased progressively to very low levels. Thus, rats were faced with temptation to "gamble", i.e. to nose-poke for a binge reward, whose delivery was omitted the majority of times. After 3weeks of testing, rats showing a clear-cut profile of either gambling proneness or aversion were selected and sacrificed after the last session. A selective down-regulation of i) serotonin transporter in prefrontal cortex, ii) tyrosine hydroxylase in ventral striatum, iii) dopamine transporter in lymphocytes was evidenced in "gambler" vs "non-gambler" rats. The exposure to such operant task (compared to home-cage alone) modulated ventrostriatal but not prefrontal genes. A consistent increase of DNA methylation, in one specific CpG site at serotonin transporter gene, was evident in prefrontal cortex of "gambler" rats. Elucidation of epigenetic changes occurring during GD progression may pave the way to the development of new therapeutic strategies through specific modulation of epigenetic factors.
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http://dx.doi.org/10.1016/j.neuroscience.2016.10.041DOI Listing
January 2017

Epigenetic regulation of nociceptin/orphanin FQ and corticotropin-releasing factor system genes in frustration stress-induced binge-like palatable food consumption.

Addict Biol 2016 11 21;21(6):1168-1185. Epub 2015 Sep 21.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Italy.

Evidence suggests that binge eating may be caused by a unique interaction between dieting and stress. We developed a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after a 15-minute exposure to the sight of the palatable food (frustration stress). The aim of the present study was to investigate the regulation of the stress neurohormone corticotropin-releasing factor (CRF) system and of the nociceptin/orphanin FQ (N/OFQ) system genes in selective rat brain regions, using our animal model. Food restriction by itself seems to be responsible in the hypothalamus for the downregulation on messenger RNA levels of CRF-1 receptor, N/OFQ and its receptor (NOP). For the latter, this alteration might be due to selective histone modification changes. Instead, CRF gene appears to be upregulated in the hypothalamus as well as in the ventral tegmental area only when rats are food restricted and exposed to frustration stress, and, of relevance, these changes appear to be due to a reduction in DNA methylation at gene promoters. Moreover, also CRF-1 receptor gene resulted to be differentially regulated in these two brain regions. Epigenetic changes may be viewed as adaptive mechanisms to environmental perturbations concurring to facilitate food consumption in adverse conditions, that is, in this study, under food restriction and stressful conditions. Our data on N/OFQ and CRF signaling provide insight on the use of this binge-eating model for the study of epigenetic modifications in controlled genetic and environmental backgrounds.
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http://dx.doi.org/10.1111/adb.12303DOI Listing
November 2016

Assessing Gene Expression of the Endocannabinoid System.

Methods Mol Biol 2016 ;1412:237-46

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.

Real-time quantitative reverse transcription polymerase chain reaction (real-time qRT-PCR), a major development of PCR technology, is a powerful and sensitive gene analysis technique that revolutionized the field of measuring gene expression. Here, we describe in detail RNA extraction, reverse transcription (RT), and relative quantification of genes belonging to the endocannabinoid system in mouse, rat, or human samples.
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http://dx.doi.org/10.1007/978-1-4939-3539-0_24DOI Listing
December 2017

Gene promoter methylation and expression of Pin1 differ between patients with frontotemporal dementia and Alzheimer's disease.

J Neurol Sci 2016 Mar 3;362:283-6. Epub 2016 Feb 3.

Geriatric Unit, Department of Medical Sciences and Community Health, University of Milan, Via Pace 9, 20122 Milan, Italy; Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.

Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD) share the accumulation of fibrillar aggregates of misfolded proteins. To better understand these neurodegenerative diseases and identify biomarkers in easily accessible cells, we investigated DNA methylation at Pin1 gene promoter and its expression in peripheral blood mononuclear cells of FTD patients. We found a lower gene expression of Pin1 with a higher DNA methylation in three CpG sites at Pin1 gene promoter analysed in FTD subjects, in contrast to a higher gene expression with a lower methylation in AD subjects and controls. These data suggest an important and distinct involvement of Pin1 in these two types of dementia.
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http://dx.doi.org/10.1016/j.jns.2016.02.004DOI Listing
March 2016

Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction?

Front Neurosci 2015 8;9:187. Epub 2015 Jun 8.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo Teramo, Italy ; European Center for Brain Research (CERC)/Santa Lucia Foundation Rome, Italy.

Several factors play a role in obesity (i.e., behavior, environment, and genetics) and epigenetic regulation of gene expression has emerged as a potential contributor in the susceptibility and development of obesity. To investigate the individual sensitivity to weight gain/resistance, we here studied gene transcription regulation of several hypothalamic neuropeptides involved in the control of energy balance in rats developing obesity (diet-induced obesity, DIO) or not (diet resistant, DR), when fed with a high fat diet. Rats have been followed up to 21 weeks of high fat diet exposure. After 5 weeks high fat diet exposure, the obese phenotype was developed and we observed a selective down-regulation of the orexigenic neuropeptide Y (NPY) and peroxisome proliferator-activated receptor gamma (PPAR-γ) genes. No changes were observed in the expression of the agouti-related protein (AgRP), as well as for all the anorexigenic genes under study. After long-term high fat diet exposure (21 weeks), NPY and PPAR-γ, as well as most of the genes under study, resulted not be different between DIO and DR, whereas a lower expression of the anorexigenic pro-opio-melanocortin (POMC) gene was observed in DIO rats when compared to DR rats. Moreover we observed that changes in NPY and POMC mRNA were inversely correlated with gene promoters DNA methylation. Our findings suggest that selective alterations in hypothalamic peptide genes regulation could contribute to the development of overweight in rats and that environmental factor, as in this animal model, might be partially responsible of these changes via epigenetic mechanism.
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http://dx.doi.org/10.3389/fnins.2015.00187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458694PMC
June 2015

Epigenetic and Proteomic Expression Changes Promoted by Eating Addictive-Like Behavior.

Neuropsychopharmacology 2015 Nov 6;40(12):2788-800. Epub 2015 May 6.

Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

An increasing perspective conceptualizes obesity and overeating as disorders related to addictive-like processes that could share common neurobiological mechanisms. In the present study, we aimed at validating an animal model of eating addictive-like behavior in mice, based on the DSM-5 substance use disorder criteria, using operant conditioning maintained by highly palatable chocolate-flavored pellets. For this purpose, we evaluated persistence of food-seeking during a period of non-availability of food, motivation for food, and perseverance of responding when the reward was associated with a punishment. This model has allowed identifying extreme subpopulations of mice related to addictive-like behavior. We investigated in these subpopulations the epigenetic and proteomic changes. A significant decrease in DNA methylation of CNR1 gene promoter was revealed in the prefrontal cortex of addict-like mice, which was associated with an upregulation of CB1 protein expression in the same brain area. The pharmacological blockade (rimonabant 3 mg/kg; i.p.) of CB1 receptor during the late training period reduced the percentage of mice that accomplished addiction criteria, which is in agreement with the reduced performance of CB1 knockout mice in this operant training. Proteomic studies have identified proteins differentially expressed in mice vulnerable or not to addictive-like behavior in the hippocampus, striatum, and prefrontal cortex. These changes included proteins involved in impulsivity-like behavior, synaptic plasticity, and cannabinoid signaling modulation, such as alpha-synuclein, phosphatase 1-alpha, doublecortin-like kinase 2, and diacylglycerol kinase zeta, and were validated by immunoblotting. This model provides an excellent tool to investigate the neurobiological substrate underlying the vulnerability to develop eating addictive-like behavior.
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http://dx.doi.org/10.1038/npp.2015.129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864655PMC
November 2015

Epigenetic control of skin differentiation genes by phytocannabinoids.

Br J Pharmacol 2013 Oct;170(3):581-91

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

Background And Purpose: Endocannabinoid signalling has been shown to have a role in the control of epidermal physiology, whereby anandamide is able to regulate the expression of skin differentiation genes through DNA methylation. Here, we investigated the possible epigenetic regulation of these genes by several phytocannabinoids, plant-derived cannabinoids that have the potential to be novel therapeutics for various human diseases.

Experimental Approach: The effects of cannabidiol, cannabigerol and cannabidivarin on the expression of skin differentiation genes keratins 1 and 10, involucrin and transglutaminase 5, as well as on DNA methylation of keratin 10 gene, were investigated in human keratinocytes (HaCaT cells). The effects of these phytocannabinoids on global DNA methylation and the activity and expression of four major DNA methyltransferases (DNMT1, 3a, 3b and 3L) were also examined.

Key Results: Cannabidiol and cannabigerol significantly reduced the expression of all the genes tested in differentiated HaCaT cells, by increasing DNA methylation of keratin 10 gene, but cannabidivarin was ineffective. Remarkably, cannabidiol reduced keratin 10 mRNA through a type-1 cannabinoid (CB1 ) receptor-dependent mechanism, whereas cannabigerol did not affect either CB1 or CB2 receptors of HaCaT cells. In addition, cannabidiol, but not cannabigerol, increased global DNA methylation levels by selectively enhancing DNMT1 expression, without affecting DNMT 3a, 3b or 3L.

Conclusions And Implications: These findings show that the phytocannabinoids cannabidiol and cannabigerol are transcriptional repressors that can control cell proliferation and differentiation. This indicates that they (especially cannabidiol) have the potential to be lead compounds for the development of novel therapeutics for skin diseases.
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http://dx.doi.org/10.1111/bph.12309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791996PMC
October 2013

Epigenetic mechanisms and endocannabinoid signalling.

FEBS J 2013 May 11;280(9):1905-17. Epub 2013 Feb 11.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

The endocannabinoid system, composed of endogenous lipids, their target receptors and metabolic enzymes, has been implicated in multiple biological functions in health and disease, both in the central nervous system and in peripheral organs. Despite the exponential growth of experimental evidence on the key role of endocannabinoid signalling in basic cellular processes, and on its potential exploitation for therapeutic interventions, much remains to be clarified about the respective regulatory mechanisms. Epigenetics refers to a set of post-translational modifications that regulate gene expression without causing variation in DNA sequence, endowed with a major impact on signal transduction pathways. The epigenetic machinery includes DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs. Due to the reversibility of epigenetic changes, an emerging field of interest is the possibility of an 'epigenetic therapy' that could possibly be applied also to endocannabinoids. Here, we review current knowledge of epigenetic regulation of endocannabinoid system components under both physiological and pathological conditions, as well as the epigenetic changes induced by endocannabinoid signalling.
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http://dx.doi.org/10.1111/febs.12125DOI Listing
May 2013

Differences in the endocannabinoid system of sperm from fertile and infertile men.

PLoS One 2012 17;7(10):e47704. Epub 2012 Oct 17.

School of Medicine, Centre for Public Health, Queen's University Belfast, Institute of Clinical Science, Belfast, United Kingdom.

Male infertility is a major cause of problems for many couples in conceiving a child. Recently, lifestyle pastimes such as alcohol, tobacco and marijuana have been shown to have further negative effects on male reproduction. The endocannabinoid system (ECS), mainly through the action of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) at cannabinoid (CB(1), CB(2)) and vanilloid (TRPV1) receptors, plays a crucial role in controlling functionality of sperm, with a clear impact on male reproductive potential. Here, sperm from fertile and infertile men were used to investigate content (through LC-ESI-MS), mRNA (through quantitative RT-PCR), protein (through Western Blotting and ELISA) expression, and functionality (through activity and binding assays) of the main metabolic enzymes of AEA and 2-AG (NAPE-PLD and FAAH, for AEA; DAGL and MAGL for 2-AG), as well as of their binding receptors CB(1), CB(2) and TRPV1. Our findings show a marked reduction of AEA and 2-AG content in infertile seminal plasma, paralleled by increased degradation: biosynthesis ratios of both substances in sperm from infertile versus fertile men. In addition, TRPV1 binding was detected in fertile sperm but was undetectable in infertile sperm, whereas that of CB(1) and CB(2) receptors was not statistically different in the two groups. In conclusion, this study identified unprecedented alterations of the ECS in infertile sperm, that might impact on capacitation and acrosome reaction, and hence fertilization outcomes. These alterations might also point to new biomarkers to determine male reproductive defects, and identify distinct ECS elements as novel targets for therapeutic exploitation of ECS-oriented drugs to treat male fertility problems.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047704PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474715PMC
April 2013